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Human genetic variants and age are the strongest predictors of humoral immune responses to common pathogens and vaccines

Scepanovic, Petar ; Alanio, Cécile ; Hammer, Christian ; Hodel, Flavia ; Bergstedt, Jacob LU ; Patin, Etienne ; Thorball, Christian W. ; Chaturvedi, Nimisha ; Charbit, Bruno and Abel, Laurent , et al. (2018) In Genome Medicine 10(1).
Abstract

Background: Humoral immune responses to infectious agents or vaccination vary substantially among individuals, and many of the factors responsible for this variability remain to be defined. Current evidence suggests that human genetic variation influences (i) serum immunoglobulin levels, (ii) seroconversion rates, and (iii) intensity of antigen-specific immune responses. Here, we evaluated the impact of intrinsic (age and sex), environmental, and genetic factors on the variability of humoral response to common pathogens and vaccines. Methods: We characterized the serological response to 15 antigens from common human pathogens or vaccines, in an age- and sex-stratified cohort of 1000 healthy individuals (Milieu Intérieur cohort). Using... (More)

Background: Humoral immune responses to infectious agents or vaccination vary substantially among individuals, and many of the factors responsible for this variability remain to be defined. Current evidence suggests that human genetic variation influences (i) serum immunoglobulin levels, (ii) seroconversion rates, and (iii) intensity of antigen-specific immune responses. Here, we evaluated the impact of intrinsic (age and sex), environmental, and genetic factors on the variability of humoral response to common pathogens and vaccines. Methods: We characterized the serological response to 15 antigens from common human pathogens or vaccines, in an age- and sex-stratified cohort of 1000 healthy individuals (Milieu Intérieur cohort). Using clinical-grade serological assays, we measured total IgA, IgE, IgG, and IgM levels, as well as qualitative (serostatus) and quantitative IgG responses to cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1 and 2, varicella zoster virus, Helicobacter pylori, Toxoplasma gondii, influenza A virus, measles, mumps, rubella, and hepatitis B virus. Following genome-wide genotyping of single nucleotide polymorphisms and imputation, we examined associations between ~5 million genetic variants and antibody responses using single marker and gene burden tests. Results: We identified age and sex as important determinants of humoral immunity, with older individuals and women having higher rates of seropositivity for most antigens. Genome-wide association studies revealed significant associations between variants in the human leukocyte antigen (HLA) class II region on chromosome 6 and anti-EBV and anti-rubella IgG levels. We used HLA imputation to fine map these associations to amino acid variants in the peptide-binding groove of HLA-DRβ1 and HLA-DPβ1, respectively. We also observed significant associations for total IgA levels with two loci on chromosome 2 and with specific KIR-HLA combinations. Conclusions: Using extensive serological testing and genome-wide association analyses in a well-characterized cohort of healthy individuals, we demonstrated that age, sex, and specific human genetic variants contribute to inter-individual variability in humoral immunity. By highlighting genes and pathways implicated in the normal antibody response to frequently encountered antigens, these findings provide a basis to better understand disease pathogenesis.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Age, GWAS, HLA, Human genomics, Humoral immunity, Immunoglobulins, Infection, Serology, Sex, Vaccination
in
Genome Medicine
volume
10
issue
1
article number
59
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85050618542
  • pmid:30053915
ISSN
1756-994X
DOI
10.1186/s13073-018-0568-8
language
English
LU publication?
yes
id
9d7f3ffb-ae82-4b26-a6a5-9c5c1459dcf5
date added to LUP
2018-08-17 14:54:08
date last changed
2021-11-16 12:57:59
@article{9d7f3ffb-ae82-4b26-a6a5-9c5c1459dcf5,
  abstract     = {<p>Background: Humoral immune responses to infectious agents or vaccination vary substantially among individuals, and many of the factors responsible for this variability remain to be defined. Current evidence suggests that human genetic variation influences (i) serum immunoglobulin levels, (ii) seroconversion rates, and (iii) intensity of antigen-specific immune responses. Here, we evaluated the impact of intrinsic (age and sex), environmental, and genetic factors on the variability of humoral response to common pathogens and vaccines. Methods: We characterized the serological response to 15 antigens from common human pathogens or vaccines, in an age- and sex-stratified cohort of 1000 healthy individuals (Milieu Intérieur cohort). Using clinical-grade serological assays, we measured total IgA, IgE, IgG, and IgM levels, as well as qualitative (serostatus) and quantitative IgG responses to cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1 and 2, varicella zoster virus, Helicobacter pylori, Toxoplasma gondii, influenza A virus, measles, mumps, rubella, and hepatitis B virus. Following genome-wide genotyping of single nucleotide polymorphisms and imputation, we examined associations between ~5 million genetic variants and antibody responses using single marker and gene burden tests. Results: We identified age and sex as important determinants of humoral immunity, with older individuals and women having higher rates of seropositivity for most antigens. Genome-wide association studies revealed significant associations between variants in the human leukocyte antigen (HLA) class II region on chromosome 6 and anti-EBV and anti-rubella IgG levels. We used HLA imputation to fine map these associations to amino acid variants in the peptide-binding groove of HLA-DRβ1 and HLA-DPβ1, respectively. We also observed significant associations for total IgA levels with two loci on chromosome 2 and with specific KIR-HLA combinations. Conclusions: Using extensive serological testing and genome-wide association analyses in a well-characterized cohort of healthy individuals, we demonstrated that age, sex, and specific human genetic variants contribute to inter-individual variability in humoral immunity. By highlighting genes and pathways implicated in the normal antibody response to frequently encountered antigens, these findings provide a basis to better understand disease pathogenesis.</p>},
  author       = {Scepanovic, Petar and Alanio, Cécile and Hammer, Christian and Hodel, Flavia and Bergstedt, Jacob and Patin, Etienne and Thorball, Christian W. and Chaturvedi, Nimisha and Charbit, Bruno and Abel, Laurent and Quintana-Murci, Lluis and Duffy, Darragh and Albert, Matthew L. and Fellay, Jacques and Alcover, Andres and Aschard, Hugues and Bousso, Philippe and Bruhns, Pierre and Cumano, Ana and Demangel, Caroline and Deriano, Ludovic and Di Santo, James and Dromer, Françoise and Eberl, Gérard and Enninga, Jost and Gelpi, Odile and Gomperts-Boneca, Ivo and Hasan, Milena and Leclerc, Claude and Mouquet, Hugo and Pellegrini, Sandra and Rogge, Lars and Sakuntabhai, Anavaj and Schwartz, Olivier and Schwikowski, Benno and Shorte, Spencer and Tangy, Frédéric and Ungeheuer, Marie Noëlle and Astrom, Kalla and Hercberg, Serge and Touvier, Mathilde and Lantz, Olivier and Soumelis, Vassili and Pol, Stanislas and Rausell, Antonio and Tartour, Eric and Toubert, Antoine},
  issn         = {1756-994X},
  language     = {eng},
  month        = {07},
  number       = {1},
  publisher    = {BioMed Central (BMC)},
  series       = {Genome Medicine},
  title        = {Human genetic variants and age are the strongest predictors of humoral immune responses to common pathogens and vaccines},
  url          = {http://dx.doi.org/10.1186/s13073-018-0568-8},
  doi          = {10.1186/s13073-018-0568-8},
  volume       = {10},
  year         = {2018},
}